Medulloblastoma (MB) is the most common malignant pediatric brain cancer. While the bulk of patients respond to multimodal therapy, significant treatment induced morbidity, and relapse (which almost always results in death) remain significant barriers in the clinical management of these patients. Thus, significant effort has gone into identifying novel targeted therapies for this cancer that both shrink the primary tumor and prevent relapse. One of these compounds, vismodegib, which is FDA-approved for metastatic basal cell carcinoma patients, has shown promise in various clinical trials for hedgehog (HH) subgroup of MB patients. Our unpublished results, along with recently published data from the Dirks group, suggests that a population of MB cancer stem cells (CSC) in HH driven MB is refractory to vismodegib, an observation likely to lead to MB recurrence in patients treated with this SMO inhibitor. Thus, this class of inhibitors may only target the tumor bulk whil leaving the cancer stem cell reservoir, which is likely responsible for tumor relapse, untouched. We focus our work in finding alternative targets to SMO for CSCs eradication within HH subgroup of MB. New candidate treatments for MB targeting CSC reservoir will be screened ex vivo on Ptch1, p53-/- CSCs cultures (Aim 1). Selected therapeutic approach will be combined with vismodegib on the ND2:SmoA1 murine model of MB to study tumor-free survival in Aim 2. Relevance of our findings in murine models of MB will be further validated in a PTCH1 driven human MB model (Aim 3). Our long-term goal is to develop a therapeutic strategy that shrinks primary tumor and targets CSC reservoir.